title: Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo.
abstract: BACKGROUND
  The mechanisms by which PAI-1 biosynthesis is altered during stress have not been fully elucidated. Studies suggest a major role for neuro-peptidergic modulation of the stress response by PACAP (pituitary adenylate cyclase-activating polypeptide), a member of the VIP/secretin/glucagon family.
  
  
  OBJECTIVE
  We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo.
  
  
  METHODS
  PAI-1 gene expression was monitored by RT-PCR in adrenal glands harvested from C57BL/6J mice that were unstressed, or subjected to restraint stress for 2 h, or treated with PACAP.
  
  
  RESULTS
  PAI-1 mRNA expression was markedly increased in adrenals from stressed mice. Restraint stress resulted in much smaller increments in adrenal tPA mRNA, suggesting that local adrenal tPA/PAI-1 biosynthetic balance is markedly altered by stress. The observed increases in PAI-1mRNA during stress were substantially blunted (55 ± 4%, P < 0.001) by pretreatment with the specific PACAP receptor antagonist, PACAP6-38, compared with pretreatment with vehicle. Administration of the agonist PACAP1-38 alone resulted in a dose-dependent increase in tissue PAI-1 mRNA. PACAP1-38 administration also resulted in substantial increases in plasma PAI-1 antigen and active PAI-1 concentrations that were significantly greater in male mice than in female mice.
  
  
  CONCLUSIONS
  We conclude that adrenal PAI-1 mRNA expression is markedly increased by stress, and that the PACAP peptidergic signaling pathway plays a major role in mediating the stress-induced increase in PAI-1 biosynthesis.
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, CA, USA; Veterans Administration San Diego Healthcare System, San Diego, CA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Gingles
authors.forename: H
authors.initials: H
authors.lastname: Bai
authors.forename: L A
authors.initials: LA
authors.lastname: Miles
authors.forename: R J
authors.initials: RJ
authors.lastname: Parmer
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017395:Plasminogen Activator Inhibitor 1
keywords: Physiological; Pituitary adenylate cyclase-activating polypeptide; Plasminogen activator inhibitor-1; Stress; Sympathetic Nervous System; tissue plasminogen activator